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How a Subfamily of Radical S-Adenosylmethionine Enzymes Became a Mainstay of Ribosomally Synthesized and Post-translationally Modified Peptide Discovery

  • Aigera Mendauletova
    Aigera Mendauletova
    Department of Chemistry and Biochemistry, University of Denver, Denver, Colorado 80210, United States
  • Anastasiia Kostenko
    Anastasiia Kostenko
    Department of Chemistry and Biochemistry, University of Denver, Denver, Colorado 80210, United States
  • Yi Lien
    Yi Lien
    Department of Chemistry and Biochemistry, University of Denver, Denver, Colorado 80210, United States
    More by Yi Lien
  • , and 
  • John Latham*
    John Latham
    Department of Chemistry and Biochemistry, University of Denver, Denver, Colorado 80210, United States
    *Email: [email protected]; Tel.: +1 303 871 2533; Fax: +1 303 871 2254.
    More by John Latham
Cite this: ACS Bio Med Chem Au 2022, 2, 1, 53–59
Publication Date (Web):December 2, 2021
https://doi.org/10.1021/acsbiomedchemau.1c00045

Copyright © 2021 The Authors. Published by American Chemical Society. This publication is licensed under

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Abstract

Radical S-adenosylmethionine (rSAM) enzymes are a large and diverse superfamily of enzymes, some of which are known to participate in the biosynthesis of ribosomally synthesized and post-translationally modified peptides (RiPPs). Specifically, a subfamily of rSAM proteins with an elongated C-terminus known as a SPASM domain have become a fixation in the discovery of new RiPP natural products. Arguably, a structural study, a bioinformatic study, and a functional study built the foundation of the research for rSAM-SPASM-protein-modified RiPPs. In this Review, we focus on these three studies and how they initiated what has become an increasingly productive field. In addition, we discuss the current state of RiPPs that depends on rSAM-SPASM proteins and provide guidelines to consider in future research. Lastly, we discuss how genome mining tools have become a powerful means to identify and predict new RiPP natural products. Despite the state of our current knowledge, we do not completely understand the relationship of rSAM-SPASM chemistry, substrate recognition, and the structure–function relationship as it pertains to RiPP biosynthesis, and as such, there remain many interesting findings waiting to be discovered in the future.

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Introduction

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Ribosomally synthesized and post-translationally modified peptides (RiPPs) have emerged as a structurally diverse class of secondary metabolites. (1) Interest in RiPPs has arisen due to their immense distribution in bacteria, their potential engineer ability, and their potential as a source of new therapeutics. (3) RiPP production begins with a genetically encoded precursor peptide being synthesized by the ribosome. Following its synthesis, modifying enzymes sequentially process the precursor peptide, ultimately yielding the mature RiPP (Figure 1). (2) Precursor peptides usually contain a N-terminal leader sequence that is recognized and bound by post-translationally modifying enzymes and/or a pathway-associated RiPP recognition element. (3−6) The classification of RiPPs is defined by the types of modifications installed on the peptide, which are carried out by the modifying enzymes.

Figure 1

Figure 1. (A) Representation of RiPP biosynthesis where a precursor peptide is modified by biosynthetic genes resulting in a mature natural product.

One family of enzymes that has become increasingly common in RiPP maturation is the radical S-adenosylmethionine (rSAM) superfamily. rSAM enzymes have been shown to catalyze a remarkable range of post-translational modifications on RiPP precursor peptides, oftentimes using unprecedented chemical strategies to modify peptides into complex natural products. (7) rSAM enzymes are effective, because they utilize an [4Fe-4S] cluster to reductively cleave SAM, generating a 5′-deoxyadenosyl radical (Figure 2A). The 5′-deoxyadenosyl radical abstracts a hydrogen atom from the peptide substrate, leading to the formation of an alkyl radical (Figure 2B). Subsequently, the alkyl radical recombines with an electron-rich functional group, leading to various outcomes. The types of post-translational modifications that have been observed include, but are not limited to, the formation of intramolecular carbon–carbon bonds, carbon–sulfur bonds, carbon–oxygen bonds, and epimerization, among others, on the precursor peptide. As a result of these modifications, rSAM-dependent natural products have been shown to be important biological molecules such as antibiotics, (8,9) essential redox cofactors, (10,11) and quorum sensing molecules, (12,13) among others. Here, we discuss how a subfamily of rSAM enzymes, rSAM-SPASM proteins, has become a focus in the study of RiPP biosynthesis, RiPP bioinformatics, and the coinage of interesting RiPP names.

Figure 2

Figure 2. (A) Schematic representation of the homolytic cleavage of SAM resulting in a 5′-deoxyadenosyl radical (5′-dA●). (B) Mechanistic scheme for rSAM-enzyme-catalzyed bond formation.

From the Foundation up

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Arguably, the most transformational set of studies in the rSAM-dependent RiPP field has involved a protein structure, a bioinformatic study, and a protein function. To begin with, the rSAM protein structure referred to stemmed from the study of sulfatase maturation in bacteria. For anaerobic sulfatase to be functional, it must first undergo post-translational oxidation of serine or cysteine to form the catalytic residue α-formylglycine (FGly). (14,15) In prokaryotes, the enzyme performing this oxidation was found to be a member of the rSAM superfamily, AtsB. (16) AtsB was shown to oxidize serine through a 5′-deoxyadenosyl-radical-mediated abstraction of the Cβ-hydrogen yielding an alkyl radical. (16) Loss of an electron and proton through an unknown mechanism results in the formation of FGly. (17) From these pioneering studies, related enzymes with a similar function have been classified as the anaerobic sulfatase maturating enzymes (AnSMEs) subfamily. (18) Structural characterization of AnSME revealed the protein to contain an elongated C-terminal domain that coordinates two auxiliary [4Fe-4S] clusters, in addition to the rSAM [4Fe-4S] cluster bound by the TIM barrel domain (Figure 3). (19) This extra C-terminal domain is annotated as a SPASM domain, named after the founding members subtilosin A, pyrroloquinoline quinone, anaerobic sulfatase, and mycofactocin. (20,21)

Figure 3

Figure 3. Crystal structure of AnSME (PDBID: 4K37) showing the TIM barrel domain (blue), SPASM domain (red), and other significant features of the prototypical rSAM-SPASM protein.

Although AnSME is not an RiPP maturase, its structure is homologous to RiPP-modifying rSAM-SPASM enzymes and thus has been pertinent to the RiPP field. Interestingly, AnSME has structural homology with another C-terminal extension called a Twitch domain. The Twitch domain, found in BtrN and MoaA, is a truncated SPASM domain that binds a single auxiliary Fe-S cluster. (22,23) The scope of this Review is focused on rSAM-SPASM enzymes and the rSAM-Twitch enzymes SkfB and TqqB. We include SkfB and TqqB because of their similarities in chemistry to rSAM-SPASM enzymes. Since publication of the AnSME structure, only three additional rSAM-SPASM proteins, out of ∼60 000 annotated in the Interpro database (IPR023885), have had their structures solved (PqqE, SuiB, and CteB). Notably, the conventional thought is that the SPASM domain binds two auxiliary [4Fe-4S] clusters; however, SPASM domains have also been reported to bind a [2Fe-2S] cluster in place of one auxiliary [4Fe-4S] cluster. (24) Regardless of the composition, a common role for auxiliary iron-sulfur clusters in RiPP modifications has not yet been definitively determined. However, it has been proposed that auxiliary clusters participate in substrate binding and/or electron shuttling. (25,26) For instance, MftC employs auxiliary clusters to catalyze two distinct reactions, oxidative and redox-neutral, on the precursor peptide. (26) Specifically, it is thought that close midpoint potential values of auxiliary clusters allow for the reversible electron transfer between each cluster. (27) A recent study of SuiB suggests a similar role. (28) By trapping the reaction intermediates and characterizing them by electromagnetic resonance spectroscopy, Balo et. al provided evidence that the auxiliary cluster I (Aux I) is the oxidant of Lys-Trp·. (28) In addition, it was suggested that substrate binding regulates the redox potential of Aux I and rSAM. (28) Considering the range of modifications that rSAM-SPASM proteins are capable of, the function(s) of the auxiliary clusters are likely to be system-dependent.
While the structure of AnSME was being elucidated, Haft and Basu reported on the association of rSAM-SPASM proteins to biosynthetic pathways that encoded for a peptide. (21) At the time, it was established that the redox cofactor, pyrroloquinoline quinone (PQQ), was synthesized from the precursor peptide PqqA. (29) In addition, it was known that the pqq biosynthetic gene cluster encoded for a rSAM-SPASM protein, PqqE, which was later shown to install a C–C cross-link between a conserved Tyr and Glu on the peptide PqqA. (30,24) The association of a peptide and a rSAM-SPASM protein, along with other bioinformatic evidence, led Haft to discover the mycofactocin (MFT) biosynthetic pathway. (31) Like PQQ, the redox cofactor MFT is synthesized from a precursor peptide and hinges on a critical transformation catalyzed by the rSAM-SPASM enzyme MftC. (32,33) Expanding on the association with peptides, Haft and Basu leveraged rSAM-SPASM proteins as molecular markers to discover new multicomponent (>2 modifying enzymes) RiPP biosynthetic pathways. (21) Their approach used partial phylogenetic profiling and hidden Markov models (HMMs) to identify rSAM-SPASM proteins that were genetically clustered with putative precursor peptides. (21) From this study, Haft and Basu identified five previously unknown RiPP natural product families that rely on rSAM-SPASM enzymes, some of which have been experimentally validated. (34,35) In addition, Haft and Basu built a collection of 68 protein subfamilies based on HMMs that are nonoverlapping and functionally distinct. (21) The abundance of rSAM-SPASM proteins and their association with peptides led Haft and Basu to postulate that rSAM-SPASM proteins are commonplace in RiPP biosynthesis, a notion that is coming to fruition.
A third major influence in the rSAM-dependent field was the study of AlbA and its involvement in synthesis of subtilosin A. (36−38) Subtilosin A is a bacteriocin that is comprised of a circular peptide containing three intramolecular thioether bridges. (36−38) Installation of the thioether bonds in subtilosin A is carried out by the rSAM-SPASM enzyme AlbA. Similar to AnSME, AlbA was found to bind three [4Fe-4S] clusters and catalyzes the 5′-deoxyadenosyl-radical-mediated hydrogen abstraction from the precursor peptide, in this case SboA. (39) Unlike AnSME, AlbA was shown to abstract hydrogen from a Cα, forming the initial alkyl radical. (25) Subsequent radical recombination with the thiol/thiolate of cysteine and loss of an electron and proton forms the intramolecular thioether bond. RiPPs that contain Cα-S bonds are classified as sactipeptides (40) (sulfur-to-alpha carbon thioether cross-linked peptides) and include sporulation killing factor (SKF), (41) the thuricin family, (42,43) ruminococcin C, (44)six-cysteines-in-forty-five (SCIFF), (34) and streptosactin. (45) The pivotal study of AlbA, together with the bioinformatic study discussed above, effectively launched the growing field of rSAM-dependent RiPPs.

Expanding the Realm of rSAM-SPASM-Derived RiPPs

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Following the publication of AlbA, the Marahiel group continued to be prolific in the discovery of sactipeptide biosynthesis. (39) They reported on SkfB, demonstrating that it catalyzed the formation of a thioether bond between a Cα-S bond on the precursor peptide to SKF (41) and on ThnB, showing that it installed a Cα-S bond on the precursor peptide of thuricin H. (46) Soon after, the functions of Tte1186, (34) CteB, (47) and RumC, (44) among others, were discovered. While reports of Cα-S thioether bridges were predominant in the early stages of rSAM-dependent RiPP discovery, it should be noted that Cβ-S and Cγ-S bonds, or ranthipeptides (radical non-α-thioether peptides), have since become increasingly common. The first rSAM-SPASM enzyme to catalyze non-Cα-S thioether bonds was QhpD. (48) QhpD installs both Cβ-S and Cγ-S thioether bonds during the maturation of the γ-subunit (QhpC) of quinohemoprotein amine dehydrogenase. (48) The family of rSAM-SPASM enzymes involved in ranthipeptide biosynthesis has since expanded to include NxxcB (49) and PapB. (50) While sacti/ranthipeptides predominated early on, a second class of rSAM-dependent RiPPs has emerged.
Carbon–carbon bonds are not trivial to make; yet, rSAM-SPASM proteins have made them commonplace. The first reported in vitro C–C bond formation by a rSAM-SPASM in RiPP biosynthesis involved streptide. (51,52) Streptide is a quorum sensing molecule that is synthesized from the precursor peptide, StrA, by the str gene cluster. (52) Within the cluster, the rSAM-SPASM protein, StrB, was shown to install a Cβ-C7 bond between Lys and Trp, yielding a cyclophane. (51) Soon after, a PqqE was reported to catalyze the formation of a Cγ-C3 bond between Glu and Tyr on the precursor peptide PqqA, a critical step in the formation of PQQ. (24) More recently, XyeB, GrrB, FxsB, WgkB, and RrrB have all been reported to catalyze the formation of cyclophanes on their respective precursor peptide. (35,53−55) The linkages from nonaromatic carbons can occur from Cα, Cβ, Cγ, or Cδ and typically are attached to the C3 of Tyr or, less discriminately, to C4–C8 of Trp. From these studies, it is becoming more apparent that rSAM-SPASM proteins have been recruited to install cyclophanes in RiPP biosynthesis. An outlier in the formation of C–C bonds is MftC. As mentioned earlier, MftC is involved in the biosynthesis of the redox cofactor MFT.
Table 1. Current List of Known rSAM-SPASM Proteins and Their Respective Products (57585961)
Currently, it is the only rSAM-SPASM protein involved in C–C bond formation that does not yield a cyclophane. Instead, two independent studies demonstrated that MftC catalyzes the oxidative decarboxylation of the C-terminus of MftA, resulting in the α/β unsaturated tyramine (MftA**). (32,33) However, mechanistic studies later demonstrated that MftC catalyzes a two-step reaction. Following the decarboxylation, MftC installs a lactam moiety by catalyzing the C–C bond formation between the Cβ of the penultimate Val and the Cα of the former Tyr. (10) While MftC is the outlier in the family of C–C-bond-forming rSAM-SPASM enzymes, it promises that potentially unusual and difficult post-translational modifications are to come. Lastly, rSAM-SPASM proteins have been shown to install C–O bonds on RiPP precursor peptides. Recently, the Seyedsayamdost group reported on the formation of an aliphatic ether in a streptococcal quorum sensing molecule encoded by the tqq biosynthetic gene cluster. (12) TqqB was shown to catalyze the formation of a C–O bond between a Thr-derived alcohol and the Cα of an adjacent Gln on the precursor peptide TqqA. (12)
Now that a foundation has been established for rSAM-SPASM enzymes and their involvement in RiPP biosynthesis, broad guidelines can be followed for investigating new rSAM-SPASM enzymes and pathways:
(1)

In the case of multicomponent RiPP biosynthetic gene clusters (>2 modifying enzymes), the rSAM-SPASM protein generally acts on the peptide first, followed by a peptidase. Rationale for this comes from both the PQQ and MFT biosynthetic pathways, where difficult chemical transformations occur on the peptide. Once the skeleton or topology is set on the peptide, it can be freed and modified by other enzymes.

(2)

Peptide-derived alkyl radical generation occurs on sp3 carbons. While this guideline could change in the future, all reports of rSAM-SPASM enzymes to date begin with alkyl radical formation on sp3 carbons.

(3)

In general, rSAM-SPASM proteins catalyze oxidative reactions, and alkyl radicals combine with electron-rich (e.g., S or O or sp2 carbon) moieties to form bonds. The only exception thus far is MftC, which catalyzes a decarboxylation reaction and a redox-neutral C–C bond formation.

The rSAM-SPASM Story Continues to Evolve

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We now know that rSAM-SPASM enzymes are widely used peptide-modifying enzymes, with expanding functionality. The development of new bioinformatic tools has led genome-based discovery of rSAM-dependent RiPPs and has been successfully employed in the discovery of sactipeptides, (47) ranthipeptides, (60) and ryptides, (55) to name a few. Different strategies have been implemented for RiPP mining, such as targeting conserved tailoring enzymes (62−64) or targeting the precursor peptide in their search. (65) For example, BAGEL performs a rule-based strategy, where it implements six-frame translation, which is used to search for the motifs and core peptides and classifies them into the RiPPs class. (66,67) The core peptide is detected by homology to the already known core peptides or the expected properties of the given class. (66) In contrast, RODEO implements profile HMM-based local genomic analysis and precursor peptide/structure prediction by implementing heuristic scoring, motif analysis, and machine learning to detect RiPPs. (65) Notably, the sactipeptide RiPP biosynthetic gene cluster was mapped via the rSAM-SPASM enzymes, which catalyze the sactionine bond by employing the recent improved version of RODEO 2.0. (60) A search was performed to identify candidate proteins using rSAM-SPASM sequences of known sactipeptides (AlbA, SkfB, ThnB, ThnC) and two SCIFFs (CteB, Tte1186). (60) Heuristics with support vector machine classification were employed in the putative precursor peptide search. (60) Then, a sequence similarity network (SSN) using the Enzyme Function Initiative Enzyme Similarity Tool (EFI-EST) is employed, to group the similar enzymes and distinguish them from novel RiPPs, for further precursor peptide analysis. (68) By doing so, Hudson et al. were able to characterize the sactipeptide huazacin and identify hundreds of new sactipeptide BGCs. Interestingly, the rSAM-SPASM protein responsible for the biosynthesis of huazacin is related to QhpD. (60) This association led them to determine that the SCIFF family members freyrasin and thermocellin contain S-Cβ and S-Cγ linkages, respectively. Subsequently, ranthipeptides have been designated as a new class of RiPPs, since they are structurally distinct from sactipeptides. (60) Taken together, the work performed by Hudson et al. indicates that the precursor peptide or peptide-related tailoring enzymes could be used as markers in the mining of novel RiPPs. (60,67)

Conclusion

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Despite the growing interest in rSAM-dependent RiPP natural products, little is known about the full extent of modifications that rSAM-SPASM proteins catalyze. Currently, the field has been relegated to discovering sacti/ranthipeptides, cyclophanes, and ether bonds. Do rSAM-SPASM enzymes install other modifications, and what are the “rules” that they follow? How do rSAM-SPASM enzymes recognize their substrate? Is there a common mechanism for the electrons being evacuated from the active site? What is it about rSAM-SPASM structures that dictate whether a thioether bond is formed rather than a cyclophane or an ether bond? To fully leverage the promise of RiPP mining toolsets, these questions will need to be answered.

Author Information

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  • Corresponding Author
  • Authors
    • Aigera Mendauletova - Department of Chemistry and Biochemistry, University of Denver, Denver, Colorado 80210, United States
    • Anastasiia Kostenko - Department of Chemistry and Biochemistry, University of Denver, Denver, Colorado 80210, United States
    • Yi Lien - Department of Chemistry and Biochemistry, University of Denver, Denver, Colorado 80210, United States
  • Author Contributions

    The manuscript was written through contributions of all authors.

  • Funding

    This work was supported by National Institutes of Health Grant GM 124002 and the National Science Foundation Grant 2042299 awarded to J.A.L.

  • Notes
    The authors declare no competing financial interest.

References

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This article references 68 other publications.

  1. 1
    Montalbán-López, M.; Scott, T. A.; Ramesh, S.; Rahman, I. R.; van Heel, A. J.; Viel, J. H.; Bandarian, V.; Dittmann, E.; Genilloud, O.; Goto, Y.; Grande Burgos, M. J.; Hill, C.; Kim, S.; Koehnke, J.; Latham, J. A.; Link, A. J.; Martínez, B.; Nair, S. K.; Nicolet, Y.; Rebuffat, S.; Sahl, H.-G.; Sareen, D.; Schmidt, E. W.; Schmitt, L.; Severinov, K.; Süssmuth, R. D.; Truman, A. W.; Wang, H.; Weng, J.-K.; van Wezel, G. P.; Zhang, Q.; Zhong, J.; Piel, J.; Mitchell, D. A.; Kuipers, O. P.; van der Donk, W. A. New Developments in RiPP Discovery, Enzymology and Engineering. Nat. Prod. Rep. 2021, 38 (1), 130239,  DOI: 10.1039/D0NP00027B
  2. 2
    Arnison, P. G.; Bibb, M. J.; Bierbaum, G.; Bowers, A. A.; Bugni, T. S.; Bulaj, G.; Camarero, J. A.; Campopiano, D. J.; Challis, G. L.; Clardy, J.; Cotter, P. D.; Craik, D. J.; Dawson, M.; Dittmann, E.; Donadio, S.; Dorrestein, P. C.; Entian, K.-D.; Fischbach, M. A.; Garavelli, J. S.; Göransson, U.; Gruber, C. W.; Haft, D. H.; Hemscheidt, T. K.; Hertweck, C.; Hill, C.; Horswill, A. R.; Jaspars, M.; Kelly, W. L.; Klinman, J. P.; Kuipers, O. P.; Link, A. J.; Liu, W.; Marahiel, M. A.; Mitchell, D. A.; Moll, G. N.; Moore, B. S.; Müller, R.; Nair, S. K.; Nes, I. F.; Norris, G. E.; Olivera, B. M.; Onaka, H.; Patchett, M. L.; Piel, J.; Reaney, M. J. T.; Rebuffat, S.; Ross, R. P.; Sahl, H.-G.; Schmidt, E. W.; Selsted, M. E.; Severinov, K.; Shen, B.; Sivonen, K.; Smith, L.; Stein, T.; Süssmuth, R. D.; Tagg, J. R.; Tang, G.-L.; Truman, A. W.; Vederas, J. C.; Walsh, C. T.; Walton, J. D.; Wenzel, S. C.; Willey, J. M.; van der Donk, W. A. Ribosomally Synthesized and Post-Translationally Modified Peptide Natural Products: Overview and Recommendations for a Universal Nomenclature. Nat. Prod. Rep. 2013, 30 (1), 108160,  DOI: 10.1039/C2NP20085F
  3. 3
    Latham, J. A.; Iavarone, A. T.; Barr, I.; Juthani, P. V.; Klinman, J. P. PqqD Is a Novel Peptide Chaperone That Forms a Ternary Complex with the Radical S-Adenosylmethionine Protein PqqE in the Pyrroloquinoline Quinone Biosynthetic Pathway. J. Biol. Chem. 2015, 290 (20), 1290812918,  DOI: 10.1074/jbc.M115.646521
  4. 4
    Burkhart, B. J.; Hudson, G. A.; Dunbar, K. L.; Mitchell, D. A. A Prevalent Peptide-Binding Domain Guides Ribosomal Natural Product Biosynthesis. Nat. Chem. Biol. 2015, 11 (8), 564570,  DOI: 10.1038/nchembio.1856
  5. 5
    Ortega, M. A.; Hao, Y.; Zhang, Q.; Walker, M. C.; van der Donk, W. A.; Nair, S. K. Structure and Mechanism of the TRNA-Dependent Lantibiotic Dehydratase NisB. Nature 2015, 517 (7535), 509512,  DOI: 10.1038/nature13888
  6. 6
    Oman, T. J.; van der Donk, W. A. Follow the Leader: The Use of Leader Peptides to Guide Natural Product Biosynthesis. Nat. Chem. Biol. 2010, 6 (1), 918,  DOI: 10.1038/nchembio.286
  7. 7
    Broderick, J. B.; Duffus, B. R.; Duschene, K. S.; Shepard, E. M. Radical S -Adenosylmethionine Enzymes. Chem. Rev. 2014, 114 (8), 42294317,  DOI: 10.1021/cr4004709
  8. 8
    Hudson, G. A.; Mitchell, D. A. RiPP Antibiotics: Biosynthesis and Engineering Potential. Curr. Opin. Microbiol. 2018, 45, 61,  DOI: 10.1016/j.mib.2018.02.010
  9. 9
    Rea, M. C.; Dobson, A.; O’Sullivan, O.; Crispie, F.; Fouhy, F.; Cotter, P. D.; Shanahan, F.; Kiely, B.; Hill, C.; Ross, R. P. Effect of Broad-and Narrow-Spectrum Antimicrobials on Clostridium Difficile and Microbial Diversity in a Model of the Distal Colon. Proc. Natl. Acad. Sci. U. S. A. 2011, 108, 46394644,  DOI: 10.1073/pnas.1001224107
  10. 10
    Khaliullin, B.; Ayikpoe, R.; Tuttle, M.; Latham, J. A. Mechanistic Elucidation of the Mycofactocin-Biosynthetic Radical S-Adenosylmethionine Protein, MftC. J. Biol. Chem. 2017, 292 (31), 1302213033,  DOI: 10.1074/jbc.M117.795682
  11. 11
    Shen, Y.-Q.; Bonnot, F.; Imsand, E. M.; RoseFigura, J. M.; Sjölander, K.; Klinman, J. P. Distribution and Properties of the Genes Encoding the Biosynthesis of the Bacterial Cofactor, Pyrroloquinoline Quinone. Biochemistry 2012, 51 (11), 22652275,  DOI: 10.1021/bi201763d
  12. 12
    Clark, K. A.; Bushin, L. B.; Seyedsayamdost, M. R. Aliphatic Ether Bond Formation Expands the Scope of Radical SAM Enzymes in Natural Product Biosynthesis. J. Am. Chem. Soc. 2019, 141 (27), 1061010615,  DOI: 10.1021/jacs.9b05151
  13. 13
    Schramma, K. R.; Seyedsayamdost, M. R. Lysine-Tryptophan-Crosslinked Peptides Produced by Radical SAM Enzymes in Pathogenic Streptococci. ACS Chem. Biol. 2017, 12 (4), 922927,  DOI: 10.1021/acschembio.6b01069
  14. 14
    Fang, Q.; Peng, J.; Dierks, T. Post-Translational Formylglycine Modification of Bacterial Sulfatases by the Radical S-Adenosylmethionine Protein AtsB. J. Biol. Chem. 2004, 279 (15), 1457014578,  DOI: 10.1074/jbc.M313855200
  15. 15
    Berteau, O.; Guillot, A.; Benjdia, A.; Rabot, S. A New Type of Bacterial Sulfatase Reveals a Novel Maturation Pathway in Prokaryotes. J. Biol. Chem. 2006, 281 (32), 2246422470,  DOI: 10.1074/jbc.M602504200
  16. 16
    Szameit, C.; Miech, C.; Balleininger, M.; Schmidt, B.; von Figura, K.; Dierks, T. The Iron Sulfur Protein AtsB Is Required for Posttranslational Formation of Formylglycine in the Klebsiella Sulfatase. J. Biol. Chem. 1999, 274 (22), 1537515381,  DOI: 10.1074/jbc.274.22.15375
  17. 17
    Grove, T. L.; Lee, K.-H.; St. Clair, J.; Krebs, C.; Booker, S. J. In Vitro Characterization of AtsB, a Radical SAM Formylglycine-Generating Enzyme That Contains Three [4Fe-4S] Clusters. Biochemistry 2008, 47 (28), 75237538,  DOI: 10.1021/bi8004297
  18. 18
    Grove, T. L.; Ahlum, J. H.; Qin, R. M.; Lanz, N. D.; Radle, M. I.; Krebs, C.; Booker, S. J. Further Characterization of Cys-Type and Ser-Type Anaerobic Sulfatase Maturating Enzymes Suggests a Commonality in the Mechanism of Catalysis. Biochemistry 2013, 52 (17), 28742887,  DOI: 10.1021/bi400136u
  19. 19
    Goldman, P. J.; Grove, T. L.; Sites, L. A.; McLaughlin, M. I.; Booker, S. J.; Drennan, C. L. X-Ray Structure of an AdoMet Radical Activase Reveals an Anaerobic Solution for Formylglycine Posttranslational Modification. Proc. Natl. Acad. Sci. U. S. A. 2013, 110 (21), 85198524,  DOI: 10.1073/pnas.1302417110
  20. 20
    Haft, D. H.; Selengut, J. D.; Richter, R. A.; Harkins, D.; Basu, M. K.; Beck, E. TIGRFAMs and Genome Properties in 2013. Nucleic Acids Res. 2012, 41 (D1), D387D395,  DOI: 10.1093/nar/gks1234
  21. 21
    Haft, D. H.; Basu, M. K. Biological Systems Discovery In Silico: Radical S -Adenosylmethionine Protein Families and Their Target Peptides for Posttranslational Modification. J. Bacteriol. 2011, 193 (11), 27452755,  DOI: 10.1128/JB.00040-11
  22. 22
    Grell, T. A. J.; Goldman, P. J.; Drennan, C. L. SPASM and Twitch Domains in S-Adenosylmethionine (SAM) Radical Enzymes. J. Biol. Chem. 2015, 290 (7), 39643971,  DOI: 10.1074/jbc.R114.581249
  23. 23
    Goldman, P. J.; Grove, T. L.; Booker, S. J.; Drennan, C. L. X-Ray Analysis of Butirosin Biosynthetic Enzyme BtrN Redefines Structural Motifs for AdoMet Radical Chemistry. Proc. Natl. Acad. Sci. U. S. A. 2013, 110 (40), 1594915954,  DOI: 10.1073/pnas.1312228110
  24. 24
    Barr, I.; Latham, J. A.; Iavarone, A. T.; Chantarojsiri, T.; Hwang, J. D.; Klinman, J. P. Demonstration That the Radical S-Adenosylmethionine (SAM) Enzyme PqqE Catalyzes de Novo Carbon-Carbon Cross-Linking within a Peptide Substrate PqqA in the Presence of the Peptide Chaperone PqqD. J. Biol. Chem. 2016, 291 (17), 88778884,  DOI: 10.1074/jbc.C115.699918
  25. 25
    Benjdia, A.; Guillot, A.; Lefranc, B.; Vaudry, H.; Leprince, J.; Berteau, O. Thioether Bond Formation by SPASM Domain Radical SAM Enzymes: C α H-Atom Abstraction in Subtilosin A Biosynthesis. Chem. Commun. 2016, 52 (37), 62496252,  DOI: 10.1039/C6CC01317A
  26. 26
    Ayikpoe, R.; Ngendahimana, T.; Langton, M.; Bonitatibus, S.; Walker, L. M.; Eaton, S. S.; Eaton, G. R.; Pandelia, M.-E.; Elliott, S. J.; Latham, J. A. Spectroscopic and Electrochemical Characterization of the Mycofactocin Biosynthetic Protein, MftC, Provides Insight into Its Redox Flipping Mechanism. Biochemistry 2019, 58 (7), 940950,  DOI: 10.1021/acs.biochem.8b01082
  27. 27
    Ayikpoe, R. S.; Latham, J. A. MftD Catalyzes the Formation of a Biologically Active Redox Center in the Biosynthesis of the Ribosomally Synthesized and Post-Translationally Modified Redox Cofactor Mycofactocin. J. Am. Chem. Soc. 2019, 141 (34), 1358213591,  DOI: 10.1021/jacs.9b06102
  28. 28
    Balo, A. R.; Caruso, A.; Tao, L.; Tantillo, D. J.; Seyedsayamdost, M. R.; Britt, R. D. Trapping a Cross-Linked Lysine-Tryptophan Radical in the Catalytic Cycle of the Radical SAM Enzyme SuiB. Proc. Natl. Acad. Sci. U. S. A. 2021, 118 (21), e2101571118  DOI: 10.1073/pnas.2101571118
  29. 29
    Goosen, N.; Huinen, R. G.; van de Putte, P. A 24-Amino-Acid Polypeptide Is Essential for the Biosynthesis of the Coenzyme Pyrrolo-Quinoline-Quinone. J. Bacteriol. 1992, 174 (4), 14261427,  DOI: 10.1128/jb.174.4.1426-1427.1992
  30. 30
    Felder, M.; Gupta, A.; Verma, V.; Kumar, A.; Qazi, G. N.; Cullum, J. The Pyrroloquinoline Quinone Synthesis Genes of Gluconobacter Oxydans. FEMS Microbiol. Lett. 2000, 193 (2), 231236,  DOI: 10.1016/S0378-1097(00)00487-0
  31. 31
    Haft, D. H. Bioinformatic Evidence for a Widely Distributed, Ribosomally Produced Electron Carrier Precursor, Its Maturation Proteins, and Its Nicotinoprotein Redox Partners. BMC Genomics 2011, 12 (1), 121,  DOI: 10.1186/1471-2164-12-21
  32. 32
    Khaliullin, B.; Aggarwal, P.; Bubas, M.; Eaton, G. R.; Eaton, S. S.; Latham, J. A. Mycofactocin Biosynthesis: Modification of the Peptide MftA by the Radical S-Adenosylmethionine Protein MftC. FEBS Lett. 2016, 590 (16), 25382548,  DOI: 10.1002/1873-3468.12249
  33. 33
    Bruender, N. A.; Bandarian, V. The Radical S -Adenosyl-l -Methionine Enzyme MftC Catalyzes an Oxidative Decarboxylation of the C-Terminus of the MftA Peptide. Biochemistry 2016, 55 (20), 28132816,  DOI: 10.1021/acs.biochem.6b00355
  34. 34
    Bruender, N. A.; Wilcoxen, J.; Britt, R. D.; Bandarian, V. Biochemical and Spectroscopic Characterization of a Radical S -Adenosyl-l -Methionine Enzyme Involved in the Formation of a Peptide Thioether Cross-Link. Biochemistry 2016, 55 (14), 21222134,  DOI: 10.1021/acs.biochem.6b00145
  35. 35
    Nguyen, T. Q. N.; Tooh, Y. W.; Sugiyama, R.; Nguyen, T. P. D.; Purushothaman, M.; Leow, L. C.; Hanif, K.; Yong, R. H. S.; Agatha, I.; Winnerdy, F. R.; Gugger, M.; Phan, A. T.; Morinaka, B. I. Post-Translational Formation of Strained Cyclophanes in Bacteria. Nat. Chem. 2020, 12 (11), 10421053,  DOI: 10.1038/s41557-020-0519-z
  36. 36
    Babasaki, K.; Takao, T.; Shimonishi, Y.; Kurahashi, K. Subtilosin A, a New Antibiotic Peptide Produced by Bacillus Subtilis 168: Isolation, Structural Analysis, and Biogenesis1. J. Biochem. 1985, 98 (3), 585603,  DOI: 10.1093/oxfordjournals.jbchem.a135315
  37. 37
    Zheng, G.; Hehn, R.; Zuber, P. Mutational Analysis of the Sbo-Alb Locus of Bacillus Subtilis: Identification of Genes Required for Subtilosin Production and Immunity. J. Bacteriol. 2000, 182 (11), 32663273,  DOI: 10.1128/JB.182.11.3266-3273.2000
  38. 38
    Kawulka, K. E.; Sprules, T.; Diaper, C. M.; Whittal, R. M.; McKay, R. T.; Mercier, P.; Zuber, P.; Vederas, J. C. Structure of Subtilosin A, a Cyclic Antimicrobial Peptide from Bacillus Subtilis with Unusual Sulfur to α-Carbon Cross-Links: Formation and Reduction of α-Thio-α-Amino Acid Derivatives. Biochemistry 2004, 43 (12), 33853395,  DOI: 10.1021/bi0359527
  39. 39
    Flühe, L.; Knappe, T. A.; Gattner, M. J.; Schäfer, A.; Burghaus, O.; Linne, U.; Marahiel, M. A. The Radical SAM Enzyme AlbA Catalyzes Thioether Bond Formation in Subtilosin A. Nat. Chem. Biol. 2012, 8 (4), 350357,  DOI: 10.1038/nchembio.798
  40. 40
    Murphy, K.; O’Sullivan, O.; Rea, M. C.; Cotter, P. D.; Ross, R. P.; Hill, C. Genome Mining for Radical SAM Protein Determinants Reveals Multiple Sactibiotic-Like Gene Clusters. PLoS One 2011, 6 (7), e20852  DOI: 10.1371/journal.pone.0020852
  41. 41
    Flühe, L.; Burghaus, O.; Wieckowski, B. M.; Giessen, T. W.; Linne, U.; Marahiel, M. A. Two [4Fe-4S] Clusters Containing Radical SAM Enzyme SkfB Catalyze Thioether Bond Formation during the Maturation of the Sporulation Killing Factor. J. Am. Chem. Soc. 2013, 135 (3), 959962,  DOI: 10.1021/ja310542g
  42. 42
    Rea, M. C.; Sit, C. S.; Clayton, E.; O’Connor, P. M.; Whittal, R. M.; Zheng, J.; Vederas, J. C.; Ross, R. P.; Hill, C. Thuricin CD, a Posttranslationally Modified Bacteriocin with a Narrow Spectrum of Activity against Clostridium Difficile. Proc. Natl. Acad. Sci. U. S. A. 2010, 107 (20), 93529357,  DOI: 10.1073/pnas.0913554107
  43. 43
    Mo, T.; Ji, X.; Yuan, W.; Mandalapu, D.; Wang, F.; Zhong, Y.; Li, F.; Chen, Q.; Ding, W.; Deng, Z.; Yu, S.; Zhang, Q. Thuricin Z: A Narrow-Spectrum Sactibiotic That Targets the Cell Membrane. Angew. Chem., Int. Ed. 2019, 58 (52), 1879318797,  DOI: 10.1002/anie.201908490
  44. 44
    Balty, C.; Guillot, A.; Fradale, L.; Brewee, C.; Boulay, M.; Kubiak, X.; Benjdia, A.; Berteau, O. Ruminococcin C, an Anti-Clostridial Sactipeptide Produced by a Prominent Member of the Human Microbiota Ruminococcus Gnavus. J. Biol. Chem. 2019, 294 (40), 1451214525,  DOI: 10.1074/jbc.RA119.009416
  45. 45
    Bushin, L. B.; Covington, B. C.; Rued, B. E.; Federle, M. J.; Seyedsayamdost, M. R. Discovery and Biosynthesis of Streptosactin, a Sactipeptide with an Alternative Topology Encoded by Commensal Bacteria in the Human Microbiome. J. Am. Chem. Soc. 2020, 142 (38), 1626516275,  DOI: 10.1021/jacs.0c05546
  46. 46
    Wieckowski, B. M.; Hegemann, J. D.; Mielcarek, A.; Boss, L.; Burghaus, O.; Marahiel, M. A. The PqqD Homologous Domain of the Radical SAM Enzyme ThnB Is Required for Thioether Bond Formation during Thurincin H Maturation. FEBS Lett. 2015, 589 (15), 18021806,  DOI: 10.1016/j.febslet.2015.05.032
  47. 47
    Grove, T. L.; Himes, P. M.; Hwang, S.; Yumerefendi, H.; Bonanno, J. B.; Kuhlman, B.; Almo, S. C.; Bowers, A. A. Structural Insights into Thioether Bond Formation in the Biosynthesis of Sactipeptides. J. Am. Chem. Soc. 2017, 139 (34), 1173411744,  DOI: 10.1021/jacs.7b01283
  48. 48
    Nakai, T.; Ito, H.; Kobayashi, K.; Takahashi, Y.; Hori, H.; Tsubaki, M.; Tanizawa, K.; Okajima, T. The Radical S-Adenosyl-l-Methionine Enzyme QhpD Catalyzes Sequential Formation of Intra-Protein Sulfur-to-Methylene Carbon Thioether Bonds. J. Biol. Chem. 2015, 290 (17), 1114411166,  DOI: 10.1074/jbc.M115.638320
  49. 49
    Caruso, A.; Bushin, L. B.; Clark, K. A.; Martinie, R. J.; Seyedsayamdost, M. R. Radical Approach to Enzymatic β-Thioether Bond Formation. J. Am. Chem. Soc. 2019, 141 (2), 990997,  DOI: 10.1021/jacs.8b11060
  50. 50
    Precord, T. W.; Mahanta, N.; Mitchell, D. A. Reconstitution and Substrate Specificity of the Thioether-Forming Radical S -Adenosylmethionine Enzyme in Freyrasin Biosynthesis. ACS Chem. Biol. 2019, 14 (9), 19811989,  DOI: 10.1021/acschembio.9b00457
  51. 51
    Schramma, K. R.; Bushin, L. B.; Seyedsayamdost, M. R. Structure and Biosynthesis of a Macrocyclic Peptide Containing an Unprecedented Lysine-to-Tryptophan Crosslink. Nat. Chem. 2015, 7 (5), 431437,  DOI: 10.1038/nchem.2237
  52. 52
    Ibrahim, M.; Guillot, A.; Wessner, F.; Algaron, F.; Besset, C.; Courtin, P.; Gardan, R.; Monnet, V. Control of the Transcription of a Short Gene Encoding a Cyclic Peptide in Streptococcus Thermophilus: A New Quorum-Sensing System?. J. Bacteriol. 2007, 189 (24), 88448854,  DOI: 10.1128/JB.01057-07
  53. 53
    Ma, S.; Chen, H.; Li, H.; Ji, X.; Deng, Z.; Ding, W.; Zhang, Q. Post-Translational Formation of Aminomalonate by a Promiscuous Peptide-Modifying Radical SAM Enzyme. Angew. Chem., Int. Ed. 2021, 60 (36), 1995719964,  DOI: 10.1002/anie.202107192
  54. 54
    Bushin, L. B.; Clark, K. A.; Pelczer, I.; Seyedsayamdost, M. R. Charting an Unexplored Streptococcal Biosynthetic Landscape Reveals a Unique Peptide Cyclization Motif. J. Am. Chem. Soc. 2018, 140 (50), 1767417684,  DOI: 10.1021/jacs.8b10266
  55. 55
    Caruso, A.; Martinie, R. J.; Bushin, L. B.; Seyedsayamdost, M. R. Macrocyclization via an Arginine-Tyrosine Crosslink Broadens the Reaction Scope of Radical S -Adenosylmethionine Enzymes. J. Am. Chem. Soc. 2019, 141 (42), 1661016614,  DOI: 10.1021/jacs.9b09210
  56. 56
    Barr, I.; Stich, T. A.; Gizzi, A. S.; Grove, T. L.; Bonanno, J. B.; Latham, J. A.; Chung, T.; Wilmot, C. M.; Britt, R. D.; Almo, S. C.; Klinman, J. P. X-Ray and EPR Characterization of the Auxiliary Fe-S Clusters in the Radical SAM Enzyme PqqE. Biochemistry 2018, 57 (8), 13061315,  DOI: 10.1021/acs.biochem.7b01097
  57. 57
    Davis, K. M.; Schramma, K. R.; Hansen, W. A.; Bacik, J. P.; Khare, S. D.; Seyedsayamdost, M. R.; Ando, N. Structures of the Peptide-Modifying Radical SAM Enzyme SuiB Elucidate the Basis of Substrate Recognition. Proc. Natl. Acad. Sci. U. S. A. 2017, 114 (39), 1042010425,  DOI: 10.1073/pnas.1703663114
  58. 58
    Bruender, N. A.; Bandarian, V. SkfB Abstracts a Hydrogen Atom from C α on SkfA To Initiate Thioether Cross-Link Formation. Biochemistry 2016, 55 (30), 41314134,  DOI: 10.1021/acs.biochem.6b00598
  59. 59
    Caruso, A.; Seyedsayamdost, M. R. Radical SAM Enzyme QmpB Installs Two 9-Membered Ring Sactionine Macrocycles during Biogenesis of a Ribosomal Peptide Natural Product. J. Org. Chem. 2021, 86 (16), 1128411289,  DOI: 10.1021/acs.joc.1c01507
  60. 60
    Hudson, G. A.; Burkhart, B. J.; DiCaprio, A. J.; Schwalen, C. J.; Kille, B.; Pogorelov, T. V.; Mitchell, D. A. Bioinformatic Mapping of Radical S -Adenosylmethionine-Dependent Ribosomally Synthesized and Post-Translationally Modified Peptides Identifies New Cα, Cβ, and Cγ-Linked Thioether-Containing Peptides. J. Am. Chem. Soc. 2019, 141 (20), 82288238,  DOI: 10.1021/jacs.9b01519
  61. 61
    Morinaka, B. I.; Lakis, E.; Verest, M.; Helf, M. J.; Scalvenzi, T.; Vagstad, A. L.; Sims, J.; Sunagawa, S.; Gugger, M.; Piel, J. Natural Noncanonical Protein Splicing Yields Products with Diverse β-Amino Acid Residues. Science (Washington, DC, U. S.) 2018, 359 (6377), 779782,  DOI: 10.1126/science.aao0157
  62. 62
    Blin, K.; Shaw, S.; Kloosterman, A. M.; Charlop-Powers, Z.; van Wezel, G. P.; Medema, M. H.; Weber, T. AntiSMASH 6.0: Improving Cluster Detection and Comparison Capabilities. Nucleic Acids Res. 2021, 49 (W1), W29W35,  DOI: 10.1093/nar/gkab335
  63. 63
    Medema, M. H.; Blin, K.; Cimermancic, P.; de Jager, V.; Zakrzewski, P.; Fischbach, M. A.; Weber, T.; Takano, E.; Breitling, R. AntiSMASH: Rapid Identification, Annotation and Analysis of Secondary Metabolite Biosynthesis Gene Clusters in Bacterial and Fungal Genome Sequences. Nucleic Acids Res. 2011, 39 (suppl_2), W339W346,  DOI: 10.1093/nar/gkr466
  64. 64
    Blin, K.; Medema, M. H.; Kazempour, D.; Fischbach, M. A.; Breitling, R.; Takano, E.; Weber, T. AntiSMASH 2.0─a Versatile Platform for Genome Mining of Secondary Metabolite Producers. Nucleic Acids Res. 2013, 41 (W1), W204W212,  DOI: 10.1093/nar/gkt449
  65. 65
    Tietz, J. I.; Schwalen, C. J.; Patel, P. S.; Maxson, T.; Blair, P. M.; Tai, H.-C.; Zakai, U. I.; Mitchell, D. A. A New Genome-Mining Tool Redefines the Lasso Peptide Biosynthetic Landscape. Nat. Chem. Biol. 2017, 13 (5), 470478,  DOI: 10.1038/nchembio.2319
  66. 66
    van Heel, A. J.; de Jong, A.; Song, C.; Viel, J. H.; Kok, J.; Kuipers, O. P. BAGEL4: A User-Friendly Web Server to Thoroughly Mine RiPPs and Bacteriocins. Nucleic Acids Res. 2018, 46 (W1), W278W281,  DOI: 10.1093/nar/gky383
  67. 67
    Zhong, Z.; He, B.; Li, J.; Li, Y.-X. Challenges and Advances in Genome Mining of Ribosomally Synthesized and Post-Translationally Modified Peptides (RiPPs). Synth. Syst. Biotechnol. 2020, 5 (3), 155172,  DOI: 10.1016/j.synbio.2020.06.002
  68. 68
    Gerlt, J. A.; Bouvier, J. T.; Davidson, D. B.; Imker, H. J.; Sadkhin, B.; Slater, D. R.; Whalen, K. L. Enzyme Function Initiative-Enzyme Similarity Tool (EFI-EST): A Web Tool for Generating Protein Sequence Similarity Networks. Biochim. Biophys. Acta, Proteins Proteomics 2015, 1854 (8), 10191037,  DOI: 10.1016/j.bbapap.2015.04.015

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  • Abstract

    Figure 1

    Figure 1. (A) Representation of RiPP biosynthesis where a precursor peptide is modified by biosynthetic genes resulting in a mature natural product.

    Figure 2

    Figure 2. (A) Schematic representation of the homolytic cleavage of SAM resulting in a 5′-deoxyadenosyl radical (5′-dA●). (B) Mechanistic scheme for rSAM-enzyme-catalzyed bond formation.

    Figure 3

    Figure 3. Crystal structure of AnSME (PDBID: 4K37) showing the TIM barrel domain (blue), SPASM domain (red), and other significant features of the prototypical rSAM-SPASM protein.

  • References

    ARTICLE SECTIONS
    Jump To

    This article references 68 other publications.

    1. 1
      Montalbán-López, M.; Scott, T. A.; Ramesh, S.; Rahman, I. R.; van Heel, A. J.; Viel, J. H.; Bandarian, V.; Dittmann, E.; Genilloud, O.; Goto, Y.; Grande Burgos, M. J.; Hill, C.; Kim, S.; Koehnke, J.; Latham, J. A.; Link, A. J.; Martínez, B.; Nair, S. K.; Nicolet, Y.; Rebuffat, S.; Sahl, H.-G.; Sareen, D.; Schmidt, E. W.; Schmitt, L.; Severinov, K.; Süssmuth, R. D.; Truman, A. W.; Wang, H.; Weng, J.-K.; van Wezel, G. P.; Zhang, Q.; Zhong, J.; Piel, J.; Mitchell, D. A.; Kuipers, O. P.; van der Donk, W. A. New Developments in RiPP Discovery, Enzymology and Engineering. Nat. Prod. Rep. 2021, 38 (1), 130239,  DOI: 10.1039/D0NP00027B
    2. 2
      Arnison, P. G.; Bibb, M. J.; Bierbaum, G.; Bowers, A. A.; Bugni, T. S.; Bulaj, G.; Camarero, J. A.; Campopiano, D. J.; Challis, G. L.; Clardy, J.; Cotter, P. D.; Craik, D. J.; Dawson, M.; Dittmann, E.; Donadio, S.; Dorrestein, P. C.; Entian, K.-D.; Fischbach, M. A.; Garavelli, J. S.; Göransson, U.; Gruber, C. W.; Haft, D. H.; Hemscheidt, T. K.; Hertweck, C.; Hill, C.; Horswill, A. R.; Jaspars, M.; Kelly, W. L.; Klinman, J. P.; Kuipers, O. P.; Link, A. J.; Liu, W.; Marahiel, M. A.; Mitchell, D. A.; Moll, G. N.; Moore, B. S.; Müller, R.; Nair, S. K.; Nes, I. F.; Norris, G. E.; Olivera, B. M.; Onaka, H.; Patchett, M. L.; Piel, J.; Reaney, M. J. T.; Rebuffat, S.; Ross, R. P.; Sahl, H.-G.; Schmidt, E. W.; Selsted, M. E.; Severinov, K.; Shen, B.; Sivonen, K.; Smith, L.; Stein, T.; Süssmuth, R. D.; Tagg, J. R.; Tang, G.-L.; Truman, A. W.; Vederas, J. C.; Walsh, C. T.; Walton, J. D.; Wenzel, S. C.; Willey, J. M.; van der Donk, W. A. Ribosomally Synthesized and Post-Translationally Modified Peptide Natural Products: Overview and Recommendations for a Universal Nomenclature. Nat. Prod. Rep. 2013, 30 (1), 108160,  DOI: 10.1039/C2NP20085F
    3. 3
      Latham, J. A.; Iavarone, A. T.; Barr, I.; Juthani, P. V.; Klinman, J. P. PqqD Is a Novel Peptide Chaperone That Forms a Ternary Complex with the Radical S-Adenosylmethionine Protein PqqE in the Pyrroloquinoline Quinone Biosynthetic Pathway. J. Biol. Chem. 2015, 290 (20), 1290812918,  DOI: 10.1074/jbc.M115.646521
    4. 4
      Burkhart, B. J.; Hudson, G. A.; Dunbar, K. L.; Mitchell, D. A. A Prevalent Peptide-Binding Domain Guides Ribosomal Natural Product Biosynthesis. Nat. Chem. Biol. 2015, 11 (8), 564570,  DOI: 10.1038/nchembio.1856
    5. 5
      Ortega, M. A.; Hao, Y.; Zhang, Q.; Walker, M. C.; van der Donk, W. A.; Nair, S. K. Structure and Mechanism of the TRNA-Dependent Lantibiotic Dehydratase NisB. Nature 2015, 517 (7535), 509512,  DOI: 10.1038/nature13888
    6. 6
      Oman, T. J.; van der Donk, W. A. Follow the Leader: The Use of Leader Peptides to Guide Natural Product Biosynthesis. Nat. Chem. Biol. 2010, 6 (1), 918,  DOI: 10.1038/nchembio.286
    7. 7
      Broderick, J. B.; Duffus, B. R.; Duschene, K. S.; Shepard, E. M. Radical S -Adenosylmethionine Enzymes. Chem. Rev. 2014, 114 (8), 42294317,  DOI: 10.1021/cr4004709
    8. 8
      Hudson, G. A.; Mitchell, D. A. RiPP Antibiotics: Biosynthesis and Engineering Potential. Curr. Opin. Microbiol. 2018, 45, 61,  DOI: 10.1016/j.mib.2018.02.010
    9. 9
      Rea, M. C.; Dobson, A.; O’Sullivan, O.; Crispie, F.; Fouhy, F.; Cotter, P. D.; Shanahan, F.; Kiely, B.; Hill, C.; Ross, R. P. Effect of Broad-and Narrow-Spectrum Antimicrobials on Clostridium Difficile and Microbial Diversity in a Model of the Distal Colon. Proc. Natl. Acad. Sci. U. S. A. 2011, 108, 46394644,  DOI: 10.1073/pnas.1001224107
    10. 10
      Khaliullin, B.; Ayikpoe, R.; Tuttle, M.; Latham, J. A. Mechanistic Elucidation of the Mycofactocin-Biosynthetic Radical S-Adenosylmethionine Protein, MftC. J. Biol. Chem. 2017, 292 (31), 1302213033,  DOI: 10.1074/jbc.M117.795682
    11. 11
      Shen, Y.-Q.; Bonnot, F.; Imsand, E. M.; RoseFigura, J. M.; Sjölander, K.; Klinman, J. P. Distribution and Properties of the Genes Encoding the Biosynthesis of the Bacterial Cofactor, Pyrroloquinoline Quinone. Biochemistry 2012, 51 (11), 22652275,  DOI: 10.1021/bi201763d
    12. 12
      Clark, K. A.; Bushin, L. B.; Seyedsayamdost, M. R. Aliphatic Ether Bond Formation Expands the Scope of Radical SAM Enzymes in Natural Product Biosynthesis. J. Am. Chem. Soc. 2019, 141 (27), 1061010615,  DOI: 10.1021/jacs.9b05151
    13. 13
      Schramma, K. R.; Seyedsayamdost, M. R. Lysine-Tryptophan-Crosslinked Peptides Produced by Radical SAM Enzymes in Pathogenic Streptococci. ACS Chem. Biol. 2017, 12 (4), 922927,  DOI: 10.1021/acschembio.6b01069
    14. 14
      Fang, Q.; Peng, J.; Dierks, T. Post-Translational Formylglycine Modification of Bacterial Sulfatases by the Radical S-Adenosylmethionine Protein AtsB. J. Biol. Chem. 2004, 279 (15), 1457014578,  DOI: 10.1074/jbc.M313855200
    15. 15
      Berteau, O.; Guillot, A.; Benjdia, A.; Rabot, S. A New Type of Bacterial Sulfatase Reveals a Novel Maturation Pathway in Prokaryotes. J. Biol. Chem. 2006, 281 (32), 2246422470,  DOI: 10.1074/jbc.M602504200
    16. 16
      Szameit, C.; Miech, C.; Balleininger, M.; Schmidt, B.; von Figura, K.; Dierks, T. The Iron Sulfur Protein AtsB Is Required for Posttranslational Formation of Formylglycine in the Klebsiella Sulfatase. J. Biol. Chem. 1999, 274 (22), 1537515381,  DOI: 10.1074/jbc.274.22.15375
    17. 17
      Grove, T. L.; Lee, K.-H.; St. Clair, J.; Krebs, C.; Booker, S. J. In Vitro Characterization of AtsB, a Radical SAM Formylglycine-Generating Enzyme That Contains Three [4Fe-4S] Clusters. Biochemistry 2008, 47 (28), 75237538,  DOI: 10.1021/bi8004297
    18. 18
      Grove, T. L.; Ahlum, J. H.; Qin, R. M.; Lanz, N. D.; Radle, M. I.; Krebs, C.; Booker, S. J. Further Characterization of Cys-Type and Ser-Type Anaerobic Sulfatase Maturating Enzymes Suggests a Commonality in the Mechanism of Catalysis. Biochemistry 2013, 52 (17), 28742887,  DOI: 10.1021/bi400136u
    19. 19
      Goldman, P. J.; Grove, T. L.; Sites, L. A.; McLaughlin, M. I.; Booker, S. J.; Drennan, C. L. X-Ray Structure of an AdoMet Radical Activase Reveals an Anaerobic Solution for Formylglycine Posttranslational Modification. Proc. Natl. Acad. Sci. U. S. A. 2013, 110 (21), 85198524,  DOI: 10.1073/pnas.1302417110
    20. 20
      Haft, D. H.; Selengut, J. D.; Richter, R. A.; Harkins, D.; Basu, M. K.; Beck, E. TIGRFAMs and Genome Properties in 2013. Nucleic Acids Res. 2012, 41 (D1), D387D395,  DOI: 10.1093/nar/gks1234
    21. 21
      Haft, D. H.; Basu, M. K. Biological Systems Discovery In Silico: Radical S -Adenosylmethionine Protein Families and Their Target Peptides for Posttranslational Modification. J. Bacteriol. 2011, 193 (11), 27452755,  DOI: 10.1128/JB.00040-11
    22. 22
      Grell, T. A. J.; Goldman, P. J.; Drennan, C. L. SPASM and Twitch Domains in S-Adenosylmethionine (SAM) Radical Enzymes. J. Biol. Chem. 2015, 290 (7), 39643971,  DOI: 10.1074/jbc.R114.581249
    23. 23
      Goldman, P. J.; Grove, T. L.; Booker, S. J.; Drennan, C. L. X-Ray Analysis of Butirosin Biosynthetic Enzyme BtrN Redefines Structural Motifs for AdoMet Radical Chemistry. Proc. Natl. Acad. Sci. U. S. A. 2013, 110 (40), 1594915954,  DOI: 10.1073/pnas.1312228110
    24. 24
      Barr, I.; Latham, J. A.; Iavarone, A. T.; Chantarojsiri, T.; Hwang, J. D.; Klinman, J. P. Demonstration That the Radical S-Adenosylmethionine (SAM) Enzyme PqqE Catalyzes de Novo Carbon-Carbon Cross-Linking within a Peptide Substrate PqqA in the Presence of the Peptide Chaperone PqqD. J. Biol. Chem. 2016, 291 (17), 88778884,  DOI: 10.1074/jbc.C115.699918
    25. 25
      Benjdia, A.; Guillot, A.; Lefranc, B.; Vaudry, H.; Leprince, J.; Berteau, O. Thioether Bond Formation by SPASM Domain Radical SAM Enzymes: C α H-Atom Abstraction in Subtilosin A Biosynthesis. Chem. Commun. 2016, 52 (37), 62496252,  DOI: 10.1039/C6CC01317A
    26. 26
      Ayikpoe, R.; Ngendahimana, T.; Langton, M.; Bonitatibus, S.; Walker, L. M.; Eaton, S. S.; Eaton, G. R.; Pandelia, M.-E.; Elliott, S. J.; Latham, J. A. Spectroscopic and Electrochemical Characterization of the Mycofactocin Biosynthetic Protein, MftC, Provides Insight into Its Redox Flipping Mechanism. Biochemistry 2019, 58 (7), 940950,  DOI: 10.1021/acs.biochem.8b01082
    27. 27
      Ayikpoe, R. S.; Latham, J. A. MftD Catalyzes the Formation of a Biologically Active Redox Center in the Biosynthesis of the Ribosomally Synthesized and Post-Translationally Modified Redox Cofactor Mycofactocin. J. Am. Chem. Soc. 2019, 141 (34), 1358213591,  DOI: 10.1021/jacs.9b06102
    28. 28
      Balo, A. R.; Caruso, A.; Tao, L.; Tantillo, D. J.; Seyedsayamdost, M. R.; Britt, R. D. Trapping a Cross-Linked Lysine-Tryptophan Radical in the Catalytic Cycle of the Radical SAM Enzyme SuiB. Proc. Natl. Acad. Sci. U. S. A. 2021, 118 (21), e2101571118  DOI: 10.1073/pnas.2101571118
    29. 29
      Goosen, N.; Huinen, R. G.; van de Putte, P. A 24-Amino-Acid Polypeptide Is Essential for the Biosynthesis of the Coenzyme Pyrrolo-Quinoline-Quinone. J. Bacteriol. 1992, 174 (4), 14261427,  DOI: 10.1128/jb.174.4.1426-1427.1992
    30. 30
      Felder, M.; Gupta, A.; Verma, V.; Kumar, A.; Qazi, G. N.; Cullum, J. The Pyrroloquinoline Quinone Synthesis Genes of Gluconobacter Oxydans. FEMS Microbiol. Lett. 2000, 193 (2), 231236,  DOI: 10.1016/S0378-1097(00)00487-0
    31. 31
      Haft, D. H. Bioinformatic Evidence for a Widely Distributed, Ribosomally Produced Electron Carrier Precursor, Its Maturation Proteins, and Its Nicotinoprotein Redox Partners. BMC Genomics 2011, 12 (1), 121,  DOI: 10.1186/1471-2164-12-21
    32. 32
      Khaliullin, B.; Aggarwal, P.; Bubas, M.; Eaton, G. R.; Eaton, S. S.; Latham, J. A. Mycofactocin Biosynthesis: Modification of the Peptide MftA by the Radical S-Adenosylmethionine Protein MftC. FEBS Lett. 2016, 590 (16), 25382548,  DOI: 10.1002/1873-3468.12249
    33. 33
      Bruender, N. A.; Bandarian, V. The Radical S -Adenosyl-l -Methionine Enzyme MftC Catalyzes an Oxidative Decarboxylation of the C-Terminus of the MftA Peptide. Biochemistry 2016, 55 (20), 28132816,  DOI: 10.1021/acs.biochem.6b00355
    34. 34
      Bruender, N. A.; Wilcoxen, J.; Britt, R. D.; Bandarian, V. Biochemical and Spectroscopic Characterization of a Radical S -Adenosyl-l -Methionine Enzyme Involved in the Formation of a Peptide Thioether Cross-Link. Biochemistry 2016, 55 (14), 21222134,  DOI: 10.1021/acs.biochem.6b00145
    35. 35
      Nguyen, T. Q. N.; Tooh, Y. W.; Sugiyama, R.; Nguyen, T. P. D.; Purushothaman, M.; Leow, L. C.; Hanif, K.; Yong, R. H. S.; Agatha, I.; Winnerdy, F. R.; Gugger, M.; Phan, A. T.; Morinaka, B. I. Post-Translational Formation of Strained Cyclophanes in Bacteria. Nat. Chem. 2020, 12 (11), 10421053,  DOI: 10.1038/s41557-020-0519-z
    36. 36
      Babasaki, K.; Takao, T.; Shimonishi, Y.; Kurahashi, K. Subtilosin A, a New Antibiotic Peptide Produced by Bacillus Subtilis 168: Isolation, Structural Analysis, and Biogenesis1. J. Biochem. 1985, 98 (3), 585603,  DOI: 10.1093/oxfordjournals.jbchem.a135315
    37. 37
      Zheng, G.; Hehn, R.; Zuber, P. Mutational Analysis of the Sbo-Alb Locus of Bacillus Subtilis: Identification of Genes Required for Subtilosin Production and Immunity. J. Bacteriol. 2000, 182 (11), 32663273,  DOI: 10.1128/JB.182.11.3266-3273.2000
    38. 38
      Kawulka, K. E.; Sprules, T.; Diaper, C. M.; Whittal, R. M.; McKay, R. T.; Mercier, P.; Zuber, P.; Vederas, J. C. Structure of Subtilosin A, a Cyclic Antimicrobial Peptide from Bacillus Subtilis with Unusual Sulfur to α-Carbon Cross-Links: Formation and Reduction of α-Thio-α-Amino Acid Derivatives. Biochemistry 2004, 43 (12), 33853395,  DOI: 10.1021/bi0359527
    39. 39
      Flühe, L.; Knappe, T. A.; Gattner, M. J.; Schäfer, A.; Burghaus, O.; Linne, U.; Marahiel, M. A. The Radical SAM Enzyme AlbA Catalyzes Thioether Bond Formation in Subtilosin A. Nat. Chem. Biol. 2012, 8 (4), 350357,  DOI: 10.1038/nchembio.798
    40. 40
      Murphy, K.; O’Sullivan, O.; Rea, M. C.; Cotter, P. D.; Ross, R. P.; Hill, C. Genome Mining for Radical SAM Protein Determinants Reveals Multiple Sactibiotic-Like Gene Clusters. PLoS One 2011, 6 (7), e20852  DOI: 10.1371/journal.pone.0020852
    41. 41
      Flühe, L.; Burghaus, O.; Wieckowski, B. M.; Giessen, T. W.; Linne, U.; Marahiel, M. A. Two [4Fe-4S] Clusters Containing Radical SAM Enzyme SkfB Catalyze Thioether Bond Formation during the Maturation of the Sporulation Killing Factor. J. Am. Chem. Soc. 2013, 135 (3), 959962,  DOI: 10.1021/ja310542g
    42. 42
      Rea, M. C.; Sit, C. S.; Clayton, E.; O’Connor, P. M.; Whittal, R. M.; Zheng, J.; Vederas, J. C.; Ross, R. P.; Hill, C. Thuricin CD, a Posttranslationally Modified Bacteriocin with a Narrow Spectrum of Activity against Clostridium Difficile. Proc. Natl. Acad. Sci. U. S. A. 2010, 107 (20), 93529357,  DOI: 10.1073/pnas.0913554107
    43. 43
      Mo, T.; Ji, X.; Yuan, W.; Mandalapu, D.; Wang, F.; Zhong, Y.; Li, F.; Chen, Q.; Ding, W.; Deng, Z.; Yu, S.; Zhang, Q. Thuricin Z: A Narrow-Spectrum Sactibiotic That Targets the Cell Membrane. Angew. Chem., Int. Ed. 2019, 58 (52), 1879318797,  DOI: 10.1002/anie.201908490
    44. 44
      Balty, C.; Guillot, A.; Fradale, L.; Brewee, C.; Boulay, M.; Kubiak, X.; Benjdia, A.; Berteau, O. Ruminococcin C, an Anti-Clostridial Sactipeptide Produced by a Prominent Member of the Human Microbiota Ruminococcus Gnavus. J. Biol. Chem. 2019, 294 (40), 1451214525,  DOI: 10.1074/jbc.RA119.009416
    45. 45
      Bushin, L. B.; Covington, B. C.; Rued, B. E.; Federle, M. J.; Seyedsayamdost, M. R. Discovery and Biosynthesis of Streptosactin, a Sactipeptide with an Alternative Topology Encoded by Commensal Bacteria in the Human Microbiome. J. Am. Chem. Soc. 2020, 142 (38), 1626516275,  DOI: 10.1021/jacs.0c05546
    46. 46
      Wieckowski, B. M.; Hegemann, J. D.; Mielcarek, A.; Boss, L.; Burghaus, O.; Marahiel, M. A. The PqqD Homologous Domain of the Radical SAM Enzyme ThnB Is Required for Thioether Bond Formation during Thurincin H Maturation. FEBS Lett. 2015, 589 (15), 18021806,  DOI: 10.1016/j.febslet.2015.05.032
    47. 47
      Grove, T. L.; Himes, P. M.; Hwang, S.; Yumerefendi, H.; Bonanno, J. B.; Kuhlman, B.; Almo, S. C.; Bowers, A. A. Structural Insights into Thioether Bond Formation in the Biosynthesis of Sactipeptides. J. Am. Chem. Soc. 2017, 139 (34), 1173411744,  DOI: 10.1021/jacs.7b01283
    48. 48
      Nakai, T.; Ito, H.; Kobayashi, K.; Takahashi, Y.; Hori, H.; Tsubaki, M.; Tanizawa, K.; Okajima, T. The Radical S-Adenosyl-l-Methionine Enzyme QhpD Catalyzes Sequential Formation of Intra-Protein Sulfur-to-Methylene Carbon Thioether Bonds. J. Biol. Chem. 2015, 290 (17), 1114411166,  DOI: 10.1074/jbc.M115.638320
    49. 49
      Caruso, A.; Bushin, L. B.; Clark, K. A.; Martinie, R. J.; Seyedsayamdost, M. R. Radical Approach to Enzymatic β-Thioether Bond Formation. J. Am. Chem. Soc. 2019, 141 (2), 990997,  DOI: 10.1021/jacs.8b11060
    50. 50
      Precord, T. W.; Mahanta, N.; Mitchell, D. A. Reconstitution and Substrate Specificity of the Thioether-Forming Radical S -Adenosylmethionine Enzyme in Freyrasin Biosynthesis. ACS Chem. Biol. 2019, 14 (9), 19811989,  DOI: 10.1021/acschembio.9b00457
    51. 51
      Schramma, K. R.; Bushin, L. B.; Seyedsayamdost, M. R. Structure and Biosynthesis of a Macrocyclic Peptide Containing an Unprecedented Lysine-to-Tryptophan Crosslink. Nat. Chem. 2015, 7 (5), 431437,  DOI: 10.1038/nchem.2237
    52. 52
      Ibrahim, M.; Guillot, A.; Wessner, F.; Algaron, F.; Besset, C.; Courtin, P.; Gardan, R.; Monnet, V. Control of the Transcription of a Short Gene Encoding a Cyclic Peptide in Streptococcus Thermophilus: A New Quorum-Sensing System?. J. Bacteriol. 2007, 189 (24), 88448854,  DOI: 10.1128/JB.01057-07
    53. 53
      Ma, S.; Chen, H.; Li, H.; Ji, X.; Deng, Z.; Ding, W.; Zhang, Q. Post-Translational Formation of Aminomalonate by a Promiscuous Peptide-Modifying Radical SAM Enzyme. Angew. Chem., Int. Ed. 2021, 60 (36), 1995719964,  DOI: 10.1002/anie.202107192
    54. 54
      Bushin, L. B.; Clark, K. A.; Pelczer, I.; Seyedsayamdost, M. R. Charting an Unexplored Streptococcal Biosynthetic Landscape Reveals a Unique Peptide Cyclization Motif. J. Am. Chem. Soc. 2018, 140 (50), 1767417684,  DOI: 10.1021/jacs.8b10266
    55. 55
      Caruso, A.; Martinie, R. J.; Bushin, L. B.; Seyedsayamdost, M. R. Macrocyclization via an Arginine-Tyrosine Crosslink Broadens the Reaction Scope of Radical S -Adenosylmethionine Enzymes. J. Am. Chem. Soc. 2019, 141 (42), 1661016614,  DOI: 10.1021/jacs.9b09210
    56. 56
      Barr, I.; Stich, T. A.; Gizzi, A. S.; Grove, T. L.; Bonanno, J. B.; Latham, J. A.; Chung, T.; Wilmot, C. M.; Britt, R. D.; Almo, S. C.; Klinman, J. P. X-Ray and EPR Characterization of the Auxiliary Fe-S Clusters in the Radical SAM Enzyme PqqE. Biochemistry 2018, 57 (8), 13061315,  DOI: 10.1021/acs.biochem.7b01097
    57. 57
      Davis, K. M.; Schramma, K. R.; Hansen, W. A.; Bacik, J. P.; Khare, S. D.; Seyedsayamdost, M. R.; Ando, N. Structures of the Peptide-Modifying Radical SAM Enzyme SuiB Elucidate the Basis of Substrate Recognition. Proc. Natl. Acad. Sci. U. S. A. 2017, 114 (39), 1042010425,  DOI: 10.1073/pnas.1703663114
    58. 58
      Bruender, N. A.; Bandarian, V. SkfB Abstracts a Hydrogen Atom from C α on SkfA To Initiate Thioether Cross-Link Formation. Biochemistry 2016, 55 (30), 41314134,  DOI: 10.1021/acs.biochem.6b00598
    59. 59
      Caruso, A.; Seyedsayamdost, M. R. Radical SAM Enzyme QmpB Installs Two 9-Membered Ring Sactionine Macrocycles during Biogenesis of a Ribosomal Peptide Natural Product. J. Org. Chem. 2021, 86 (16), 1128411289,  DOI: 10.1021/acs.joc.1c01507
    60. 60
      Hudson, G. A.; Burkhart, B. J.; DiCaprio, A. J.; Schwalen, C. J.; Kille, B.; Pogorelov, T. V.; Mitchell, D. A. Bioinformatic Mapping of Radical S -Adenosylmethionine-Dependent Ribosomally Synthesized and Post-Translationally Modified Peptides Identifies New Cα, Cβ, and Cγ-Linked Thioether-Containing Peptides. J. Am. Chem. Soc. 2019, 141 (20), 82288238,  DOI: 10.1021/jacs.9b01519
    61. 61
      Morinaka, B. I.; Lakis, E.; Verest, M.; Helf, M. J.; Scalvenzi, T.; Vagstad, A. L.; Sims, J.; Sunagawa, S.; Gugger, M.; Piel, J. Natural Noncanonical Protein Splicing Yields Products with Diverse β-Amino Acid Residues. Science (Washington, DC, U. S.) 2018, 359 (6377), 779782,  DOI: 10.1126/science.aao0157
    62. 62
      Blin, K.; Shaw, S.; Kloosterman, A. M.; Charlop-Powers, Z.; van Wezel, G. P.; Medema, M. H.; Weber, T. AntiSMASH 6.0: Improving Cluster Detection and Comparison Capabilities. Nucleic Acids Res. 2021, 49 (W1), W29W35,  DOI: 10.1093/nar/gkab335
    63. 63
      Medema, M. H.; Blin, K.; Cimermancic, P.; de Jager, V.; Zakrzewski, P.; Fischbach, M. A.; Weber, T.; Takano, E.; Breitling, R. AntiSMASH: Rapid Identification, Annotation and Analysis of Secondary Metabolite Biosynthesis Gene Clusters in Bacterial and Fungal Genome Sequences. Nucleic Acids Res. 2011, 39 (suppl_2), W339W346,  DOI: 10.1093/nar/gkr466
    64. 64
      Blin, K.; Medema, M. H.; Kazempour, D.; Fischbach, M. A.; Breitling, R.; Takano, E.; Weber, T. AntiSMASH 2.0─a Versatile Platform for Genome Mining of Secondary Metabolite Producers. Nucleic Acids Res. 2013, 41 (W1), W204W212,  DOI: 10.1093/nar/gkt449
    65. 65
      Tietz, J. I.; Schwalen, C. J.; Patel, P. S.; Maxson, T.; Blair, P. M.; Tai, H.-C.; Zakai, U. I.; Mitchell, D. A. A New Genome-Mining Tool Redefines the Lasso Peptide Biosynthetic Landscape. Nat. Chem. Biol. 2017, 13 (5), 470478,  DOI: 10.1038/nchembio.2319
    66. 66
      van Heel, A. J.; de Jong, A.; Song, C.; Viel, J. H.; Kok, J.; Kuipers, O. P. BAGEL4: A User-Friendly Web Server to Thoroughly Mine RiPPs and Bacteriocins. Nucleic Acids Res. 2018, 46 (W1), W278W281,  DOI: 10.1093/nar/gky383
    67. 67
      Zhong, Z.; He, B.; Li, J.; Li, Y.-X. Challenges and Advances in Genome Mining of Ribosomally Synthesized and Post-Translationally Modified Peptides (RiPPs). Synth. Syst. Biotechnol. 2020, 5 (3), 155172,  DOI: 10.1016/j.synbio.2020.06.002
    68. 68
      Gerlt, J. A.; Bouvier, J. T.; Davidson, D. B.; Imker, H. J.; Sadkhin, B.; Slater, D. R.; Whalen, K. L. Enzyme Function Initiative-Enzyme Similarity Tool (EFI-EST): A Web Tool for Generating Protein Sequence Similarity Networks. Biochim. Biophys. Acta, Proteins Proteomics 2015, 1854 (8), 10191037,  DOI: 10.1016/j.bbapap.2015.04.015

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